Brit. J. Anaesth.

(1971), 43, 96

MANAGEMENT OF PATIENTS WITH HOMOCYSTINURIA REQUIRING

SURGERY UNDER GENERAL ANAESTHESIA
A Case Report
BY
JOHN W. CROOKE, J. F. TOWERS AND W. H. TAYIOR

SUMMARY
An 8-year-old boy with homocystinuria required a prolonged dental operation under
general anaesthesia. The successful management, without subsequent thrombo-
embolism, is described. The patient showed a partial response to treatment with
pyridoxine over a two-year period. The response was marked by a reduction in the
plasma and urinary homocystine levels and by decreased platelet adhesiveness. It is
suggested that a similar regime of pre-operative and operative management should be
considered in all affected patients undergoing surgery, since there was no increase in
platelet adhesiveness by the third postoperative day, as would normally have occurred.

Advances in diagnosis and therapy have resulted are frequently myopic and exhibit ectopia lentis;
in the increased survival of patients affected by have metaphyseal changes in the long bones; a
rare diseases. Such survival may in turn present tendency to thromboses and embolic episodes;
complications of management which were pre- convulsions; mental retardation; a high colour to
viously unknown. the cheeks; fine fair hair; knock knees; flat feet,
An example of such a disease is homocystinuria, and kyphoscoliosis. Gerritsen and Waisman
first described by Field and associates (1962), and (1966) state that diagnosis is suggested by the
independently in the same year by Gerritsen, presence of (1) ectopia lends, (2) mental retarda-
Vaughn and Waisman (1962). Studies of patients tion, (3) convulsions, (4) fine sparse hair. The
with this metabolic disorder reveal a strikingly diagnosis is confirmed by demonstration of homo-
high incidence of thrombo-embolic complications, cystine in the urine.
associated with a high mortality. These may At present treatment of homocystinuria is
occur spontaneously and, in particular, after directed toward reducing the homocystine con-
surgery often of a minor nature. tent of the urine and plasma by the administra-
Carson and colleagues (1965) presented ten tion of a diet with a low methionine content, or
cases who between them suffered more than ten of pyridoxine which acts as a co-enzyme in the
thrombo-embolic episodes; there was a fatal out- metabolic pathway of methionine (Gerritsen and
come in three cases. Henkind and Ashton (1965) Waisman, 1966; Komrower, 1969). Opportunity
reported two postoperative deaths due to to consider the operative and anaesthetic manage-
thrombo-embolism following ocular surgery. Har- ment of homocystinuria was taken when an
court (1969) reported that episodes of thrombo- 8-year-old boy known to have the disorder was
embolism are common following general anaes- referred for treatment of a dental abscess.
thesia. McDonald and associates (1964) have
demonstrated increased platelet adhesiveness in JOHN W. CROOKE, M.B., B.S., B.SC(PHYSIOI_),
affected patients, and it is to be expected that F.F.A.R.C.S.; J. F. TOWERS,* M.R.C.S., L.R.CP.,
such adhesiveness would increase in the post- F.D.S.R.C.P.S., F.F.DJLC-S.; W . H . TAYLOR, M.A., D.M.,
MJLC.P.; Department of Anaesthesia, University of
operative period. Liverpool, and the Departments of Oral Surgery and
Sufficient numbers of cases of homocystinuria Chemical Pathology, The United Liverpool Hospitals
(Royal Infirmary), Liverpool 3.
have now been described to show that the disease * Present address: Department of Oral Surgery, St
carries definite stigmata; thus affected children George's Hospital Group, London.

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 MANAGEMENT OF PATIENTS WITH HOMOCYSTINURIA 97

CASE REPORT adhesiveness. The results in table I would suggest that

treatment with pyridoxine has caused a marked diminu-
The patient was born in November 1960. and is the tion in the percentage of adhering platelets. The normal
youngest surviving child of a family in which three value of non-adhering platelets is 72 per cent or higher
male children died in infancy. One older girl and two for each of the methods used.
older brothers survived. Of the three who died, one The clinical features, as distinct from the biochemical
was stillborn, another died at 6 weeks of cerebral and haematological features, have not changed as a
thrombosis, and the third at 16 months of broncho- result of the treatment with pyridoxine; the malar flush,
pneumonia. The other surviving children do not pre- skin lividity and mental retardation are still just as
sent the clinical picture of homocystinuria. prominent.
Homocystinuria was diagnosed at the age of 7 years
as a result of a screening survey of partially sighted TABLE I
children, carried out by the Schools Medical Officers Response of plasma and urinary homocysiine levels,
of the City of Liverpool. Th; patient was known to and platelet adhesiveness, to treatment with pyridoxine
have had two attacks of epilepsy at the age of 10 hydrochloride.
months, and ectopia lends was diagnosed at the age
of 4 years 9 months. At this time two urine samples
were examined by two different laboratories and homo-
cystine was not found.
On examination, at the age of 7 years, he was 118
cm in height and weighed 22.5 kg, both measurements
being within the normal range for his years. He had
the typical fair hair of the disease with marked lividity 1§
of the skin, a malar flush (fig. 1) and slight knock knees. ?1
1
He was also severely mentally retarded.
I
Before 121
treatment 204 47*
Nov. 1967 250 3.2 148 60*
Jan. 1968 350 0.5 113
Mar. 1968 750 1.3 98 72*
May 1968 1000 1.6 65
Apr. 1968 1200 1.6 48
June 1969 1200 43.5
Pre-op 72 f
Post-op
(3 days) 76t
Homocystine is normally absent from plasma and
urine. Normal non-adhering platelets =72 per cent.
• Estimated by the rotating bulb method;
t Estimated by the glass bead method (Dacie and
Lewis, 1968).

FIG. 1
An 8-year-old boy showing the high col-
our, malar flush and fair hair typical of
patients with homocystinuria.
Treatm:nt was begun with pyridoxine hydrochloride
in November 1967, to which there has been a partial
response (table I). The dosage of pyridoxine has cur-
rently been increased to 1200 mg daily in order to see
if further lowering of the plasma and urinary homo-
cystine level can be achieved.
In addition to the biochemical features, the patient
also showed the characteristic increase in platelet
a*
Anaesthetic technique.
The operation was planned for the morning, the
drinking of water being allowed and encouraged up to
3 hours before in order to avoid pre-operative dehydra-
tion. The patient weighed 25 kg, and was premedicated
with atropine 0.4 mg intramuscularly to ensure a dry
mouth for surgery, and to encourage a fast pulse and
high cardiac output Sedatives were avoided to allow
rapid recovery postoperatively. Anaesthesia was induced
with thiopsntone 100 mg, tubocurarine 17.5 mg, nitrous
oxide and oxygen, after which a 6.5-mm non-cuffed
orotracheal tube was carefully passed, thus avoiding the
additional risk of trauma often associated with nasal
intubation. A moist throat pack was used. The correct
selection of tube fize allowed intermittent positive
pressure ventilation without a leak, and anaesthesia was
maintain^ with nitrous oxide and oxygen. Halothane
0.25-0.5 per cent was added for the first hour, from a
Fluotec vaporizer outside the circuit, to improve vaso-
dilatation and peripheral blood flow.
Immediately after induction an intravenous infusion
was set up, using an indwelling No. 18 gauge l i in.
needle in the dorsum of the left hand. 250 ml of Mac-
rodex "70^ 6 pjr cent in 5 per cent dextrose, i.e.

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 98
aDproximately one-eighth of the patient's estimated
blood volume, was infused over the next 10 min. This
volume did not cause any alteration in the pulse rate
(120 beats/min), and prevented the moderate fall in
systemic blood pressure which would otherwise have
been anticipated, the blood pressure remaining steady
at 110/75 mm Hg.
During the course of the anaesthetic the systolic
pressure and pulse rate were each prevented from
falling below 100 mm Hg and beats/min by injection
of two further increments of atropine 0.2 mg intra-
venously- A further 5.0 mg of tubocurarine were
required. The patient's legs were moved and his calves
massaged every 5-10 min, and the operating table
inclined slightly head-down for 2-3 roin on three
occasions in an attempt to improve peripheral venous
return.
On completion of the surgery muscle relaxation was
reversed with atropine 0.48 mg and neostigmine 2.0
mg which were given together intravenously. Follow-
ing extubation the blood pressure was 120/70 mm He
and pulse 112 beats/min. The drip was discontinued
before the patient left the theatre. A total volume of
325 ml of Macrodex had been infused (approximately
one-sixth of the estimated blood volume). The blood
loss was minimal. The duration of the operation was
1 hr 30 min and of anaesthesia 1 hr 55 min. The patient
was returned to the ward conscious and co-operative.
A quarter-hourly blood pressure and puke chart was
kept for the next 2 hours, and then 4-hourly.
Operative technique.
Dental procedures were carried out as follows.
(1) Fillings were inserted in three permanent molar
teeth
6 / 6
/ 6
/E
(2) Six teeth i -c-n i TVC VftTC extracted and the
o r.l;/ ub.
socket walls approximated with gut sutures.
Two hours postoperatively the patient was ambulant,
able to drink, and had passed 90 ml of urine. His Hood
pressure was 125/70 mm Hg and pulse 100 beats/min.
Monitoring of pulse and blood oressure was continued
for a further 24 hours and both remained steady. He
was given a fluid intake of approximately l i 1. for each
of the first two postoperative days. Recovery was
uneventful, and he has remained well since.
DISCUSSION
With the knowledge of fatalities in previous cases
in this disease (Carson et al., 1965; Henkind and
Ashton, 1965), due thought was given to the
prevention of postoperative thrombosis. Since it
is not known whether general anaesthesia of itself
increases the tendency to intravascular throm-
bosis, the fact that it may is sufficient ground for
its avoidance if local anaesthesia is possible and
practicable. Trauma of any degree appears to be
potentially dangerous, and should therefore be
reduced to a minimum.
In this case the fact that the patient was men-
tally retarded and that dental treatment was
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BRITISH JOURNAL OF ANAESTHESIA
needed in all quadrants of the mouth, made it
necessary to use general anaesthesia. It was there-
fore important to consider if our usual pre-
operative preparation needed modification, and
which anaesthetic technique was best suited to
the operative and postoperative requirements.
On the basis that the chances of intravascular
thrombosis would be reduced if those factors
known to stimulate it were diminished, the pre-
operative preparation, the conduct of the anaes-
thetic and the management of the early
postoperative periods were designed to promote:
(i) reduction in blood viscosity and platelet
adhesiveness; (ii) maintenance of high cardiac
output and rapid circulation time; (iii) reduction
of vascular resistance and improvement of peri-
pheral perfusion; (iv) good venous return; (v)
quick recovery and early postoperative ambula-
tion.
It was decided that the intravenous infusion of
Macrodex (dextran with a weight average mole-
cular weight of 70,000) during operation would
help to satisfy the first requirement, as well as
promoting venous return. Bennett and associates
(1966) demonstrated that infusion of dextran 70
diminished platelet adhesiveness in normal men.
Bygdeman (1967, 1969) confirmed the above re-
sults and showed that the optimal effect on
platelet "stickiness" was achieved with dextran
77.5 (a special sharp fraction with a weight
average molecular weight of 77,500). Dextrans
about this molecular weight were more effective
than dextran 40 solutions. Bennett, Dhall and
Matheson (1968) showed that infusion of Macro-
dex (dextran 70) in patients undergoing abdom-
inal surgery caused a significant reduction in
platelet adhesivness, as measured on the third
postoperative day, when compared with normal
controls. The role of platelets in thrombosis is
discussed by Hampton (1969) who mentions the
importance of other plasma factors which may
effect platelet behaviour. Ham and Slack (1967)
suggest that maximum platelet adhesivness occurs
much sooner than the tenth postoperative day, as
was widely thought, and that adhesiveness in-
creases before new platelets are formed in res-
ponse to stress.
It is of special interest that treatment with
pyridoxine achieved a normalization of the
platelet adhesiveness up to the time of surgery.
 MANAGEMENT OF PATIENTS WITH HOMOCYSTINURIA
However, of greater interest is that following
surgery the platelet adhesiveness did not increase
as was expected but in fact decreased. It is sug-
gested that this decrease was brought about by
the regime which was instituted as part of the
anaesthetic technique and, further, that this
decrease in platelet stickiness contributed to a
prevention of thrombotic complications and the
patient's uneventful recovery.
ACKNOWLEDGEMENTS
We wish to thank Dr Colin Bray and Mr John Kecnan
for their estimation of platelet adhesiveness, and Mrs
S. Simpson and Mr D. Kilshaw for the homocystine
determination.
We are indebted to Pharmacia Ltd. for financing the
printing of the colour plate.
REFERENCES
Bennett, P. K , Dhall, D. P., McKenzie, F. N., and
Matheson, N. A. (1966). Effects of dextran infu-
sion on the adhesiveness of human blood platelets.
Lancet. 2, 1001.
Matheson, N. A. (1968). Effect of dixtran
70 infusion on platelet adhesiveness after operation.
Brit. J. Surg., 55 No. 4, 289.
Bygdeman, S. (1967). Experimental studies on the anti-
thrombotic effect of dexcran. Acta. churg. scand.,
Supplement 387, 44.
(1969). Prevention and therapy of thrombo-
embolic complications with dexcran. Progr. Surg.
(floseT), 7, 114.
Carson, N. A. J., Dent, C E., Field, C M-, and Gaull,
G. E. (1965). Homocystinuria: clinical and
pathological review of ten cases. J. Pedica., 66, 565.
Dacie, J. V., and Lewis, S. M. (1968). Practical
Haematology, 4th ed., p. 323. London: Churchill.
Field, C M. B., Carson, N. A. J., Cusworth, D. C ,
Dent, C. E., and Neill, D. W. (1962). Homo-
cystinuria: a new disorder of metabolism. Abslr.
Xth Internal. Congr. Pediat., Lisbon, p. 274.
Gerritsen, T., Vaughn, J. G., and Waisman, H. A.
(1962). The identification of homocystine in the
urine. Biochctn. biophys. Res. Commun., 9, 493.
Waisman, H. A. (1966). Homocystinuria, in The
Metabolic Basis of Inherited Disease, 2nd ed. (eds.
Stanbury, J. B., Wyngaarden, J. B., and Fredrick-
son, D. S.), chap. 21, p. 423. New York: McGraw-
Hill.
Ham, J. M., and Slack, W. W. (1967). Platelet adhesive-
ness after surgery. Brit. J. Surg., 54, 385.
Hampton J. R. (1969). Platelets and thrombosis. Brit.
j . Hosp. Med., 2, No. 9, 1504.
Harcourt, R. B. (1969). Ocular manifestations of inborn
errors of metabolism. Brit. J. Hosp. Med., 2, No. 4,
831.
Henkind, P., and Ashton, N. (1965). Ocular pathology
in homocystinuria. Trans, ophthal. Soc. UJC., 85,
21.
Komrower, G. (1969). Metabolic abnormalities and
mental retardation. Brit. J. Hosp. Med., 2, No. 4,
840.
McDonald, L.. Bray, C , Love, F., and Davies, B.
(1964). Homocystinuria. thrombosis, and the blood
platelets. Lancet, I, 745.
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99
TRAITEMENT DES PATIENTS AVEC
HOMOCYSTINURIA, D E V A N T ETRE OPERES
SOUS ANESTHESIE GENERALE:
DESCRIPTION D ' U N CAS
SOMMAIRE
Un garcon de huit ans, avec homocystinuria devait
subir une intervention dentaire prolongee sous anes-
th6sie locale. Les auteurs decrivent la conduitc qu'ils ont
suivi ayec succes, sans thrombo-embolisme ulteneur.
Le patient avait durant une periode de deux ans reagi
partiellement au traitement a la pyridoxine. La response
se manifesta par une reduction des taux urinaires et
plasmatiques dTiomocystine, et par une adherence
thrombocytaire riduite. On suggcre de suivre une con-
duite pre'-operatoire et operatoire du meme genre chea
tous les patients atteints, qui doivent ctre op6res,
puisqu'au troisieme jour apres l'operation il n'y eut pas
d'augmentation de l'adherence des thrombocytes, telle
qu'elle se produit normalemcnt.
BEHANDLUNG VON PATIENTEN MIT
HOMOZYSTINURIE BEI OPERATIVEN
EINGRIFFEN I N ALLGEMEINNARK.OSE: EIN
KASUISTISCHER BEITRAG
ZUSAMMENFASSUNG
An einem acht Jahre alten Jungen mit Homozystinurie
mufite eine langer dauernde Zahnoperation in Voll-
narkose durchgefuhrt werden. Es wird die erfolgreiche
Behandlung ohne nachfolgende Thromboembofie be-
schrieben. Bei dem Patienten, der iiber 2 Jahre mit
Pyridoxin behandelt worden war, zeigte skh eine
partielle BeeinfluCung, die gekennzeichnet war dutch
eine Verminderung der Homozystin-Konzentration in
Plasma und Urin und durch eine Abnahme der
Thrombozyten-Aggregations-fahigkeit, In alien glei-
chartigen Fallen, in denen eine Operation notig ist,
sollte eine ahnliche Behandlung vor und wahrend der
Operation in Erwagung gezogen werden, da die sonset
am dritten postoperativen Tag haufig auftretende
Zunahme der Thrombozyten-Aggregations-fahigkeit
nicht beobachtet wurde.
TRATAMIENTO D E PACIENTES CON
HOMOCISTINURIA QUE NECESITAN U N A
INTERVENCION QUIRURGICA CON
ANESTESIA GENERAL: COMMUNICACION D E
UNCASO
RESUMEN
U n nirio de ocho arios de edad con homocistinuria
necesit6 una operacion dental prolongada con anestesia
generaL Se describe el tratamiento conveniente, sin
tromboembolismo subsiguiente. El paciente present6
una respuesta parcial al tratam:ento con piridoxina
durante un periodo de dos aiios. La respuesta fue
reflejada por una reducci6n de los niveles de homo-
cistina en plasma y orina, asi como una disminuci6n de
la adhesividad plaquetaria. Se propone que seria con-
veniente tener en cuenta un regimen similar de tra-
tamiento preoperatorio y operatorio en todos los
pacientes de esta Indole sometidos a intervenciones
quinirgicas, ya que al llegar el tercer dia posoprratorio
no habia ningrin incremento de la adhesividad pla-
qu:taria, como hubiera ocurrido normalmente.